Consequences of VHL Loss on Global DNA Methylome View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Claire M. Robinson, Francois Lefebvre, Betty P. Poon, Aurelie Bousard, Xiaojun Fan, Mark Lathrop, Jorg Tost, William Y. Kim, Yasser Riazalhosseini, Michael Ohh

ABSTRACT

In clear-cell renal cell carcinoma (ccRCC), loss of von Hippel-Lindau (VHL) tumour suppressor gene and reduced oxygen tension promote stabilisation of hypoxia-inducible factor (HIF) family of transcription factors, which promote changes in the expression of genes that contribute to oncogenesis. Multiple studies have demonstrated significant perturbations in DNA methylation in ccRCC via largely unclear mechanisms that modify the transcriptional output of tumour cells. Here, we show that the methylation status of the CpG dinucleotide within the consensus hypoxia-responsive element (HRE) markedly influences the binding of HIF and that the loss of VHL results in significant alterations in the DNA methylome. Surprisingly, hypoxia, which likewise promotes HIF stabilisation and activation, has relatively few effects on global DNA methylation. Gene expression analysis of ccRCC patient samples highlighted expression of a group of genes whose transcription correlated with methylation changes, including hypoxic responsive genes such as VEGF and TGF. These results suggest that the loss of VHL alters DNA methylation profile across the genome, commonly associated with and contributing to ccRCC progression. More... »

PAGES

3313

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-21524-5

DOI

http://dx.doi.org/10.1038/s41598-018-21524-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1101045842

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29463811


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